We continue to improve our understanding of the pathogenesis of pre-malignant monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM), as summarized below. First, we have shown that 27 of 30 MM tumors were preceded by an MGUS tumor, providing some of the first evidence that MM mostly, if not always, is preceded by MGUS. Significantly, in four (13%) of these patients, the MM and preceding MGUS tumors were light chain only, confirming that light chain only MGUS is a significant clinical entity, and suggesting that light chain only MM usually is preceded by light chain only MGUS and not MGUS that loses expression of IgH chains. Second, we have identified seven primary translocation partners that are present in 40% of multiple myeloma tumors and comprise three translocation groups: CYCLIN D, MAF, and MMSET/FGFR3. Third, we determined that the dysregulation of a CYCLIN D gene is an early and unifying event in MGUS and multiple myeloma. Fourth, these two early oncogenic events enabled us to propose the TC (translocation/cyclin D) classification, which appears to be applicable to all MGUS and multiple myeloma tumors, but also has been demonstrated to have significance for therapeutic decisions. Fifth, we have determined that secondary translocations, which are involved in tumor progression, have structural features and chromosomal partners that distinguish them from primary translocations. Sixth, we have determined that NFKB activation either by extrinsic ligands or by mutations in at least nine components of the classical and/or alternative NFKB pathways is important for the survival and growth of normal plasma cells as well as most MGUS and MM tumors. This suggests that MGUS and MM tumors may be addicted to this pathway, and thus sensitive to drugs that inhibit the NFKB pathway. We currently are evaluating inhibitors that target MAP3K14 (NFkB inducing kinase), a key molecule in activation of the alternative NFkB pathway that often is activated by mutations in MM tumors. Seventh, we have identified a RAS paradox, i.e., N-RAS mutations are much more prevalent in tumors that express CYCLIN D1 (22%) than in tumors that express CYCLIN D2 (4%), whereas K-RAS mutations have the same prevalence (17%) in both kinds of tumors. Although we presently do not understand this RAS paradox, it seems significant that N-RAS mutations were identified in 4 of 51 (8%) MGUS tumors, but K-RAS mutations were identified in none of the 51 MGUS tumors. It seems that K- and N-RAS are not interchangeable but actually have different roles in the pathogenesis of MM, a result that is consistent with recent reports by others that K- and N-RAS are not functionally equivalent. Eighth, we have determined that the PI3K/AKT pathway is activated in at least 20% of MM tumors, usually by overexpression of DEPTOR induced by MAF and yet to be identified mechanisms, and less often by inactivation of PTEN. Ninth, inactivation or mutation of p53, MYC/Ig rearrangements and dysregulation, and additional disruption (beyond the early dysregulation of a CYCLIN D gene) of the RB pathway appear to be relatively late progression events that are associated with increased proliferation and a poor prognosis. The RB pathway alterations are manifested by homozygous deletion of p18INK4c (10-30% of proliferative tumors and cell lines) vs an increase in the expression of p18 (60% of cell lines and proliferative tumors);this increase probably results from the fact that E2F enhances transcription of genes that increase proliferation, but also of p18. The insensitivity of the RB pathway to the inhibitory effects of p18 remains unexplained except for a small fraction of tumors that have inactivated RB1. Finally, and most recently, we have determined that cryptic rearrangements in the MYC locus that are detected by CGH, usually without involvement of an Ig locus, are present in 35% of newly diagnosed MM tumors, but more than 50% of hyperdiploid tumors and only 15% of tumors that have a t(11;14) translocation. MM tumors with the cryptic rearrangements have a significantly higher expression level of MYC (mostly monoallelic expression) than tumors not having a detectable rearrangement (which mostly have biallelic expression). This new evidence for early MYC rearrangements in some MM tumors is consistent with the increased expression of MYC in MM vs pre-malignant MGUS tumors, even for MM tumors lacking evidence of MYC rearrangement. This data also is consistent with a published animal model in which conditional dysregulation of a MYC transgene results in a high incidence of MM in an MGUS-prone mouse strain. Our new working hypothesis is that increased MYC expression, which is associated with cryptic rearrangements in the MYC locus in about 1/3 of tumors but by yet to be identified trans mechanisms in the other 2/3 of tumors is an essential event involved in the progression of pre-malignant MGUS to MM. Our prior results showing that MYC locus rearrangements, and particularly rearrangements that involve an Ig locus, often are late events suggests an additional hypothesis: tumors that have increased expression of MYC by a trans mechanism often acquire a late rearrangement of the MYC locus as the tumors become more aggressive and less dependent on the bone marrow microenvironment.